This application entitled "Targeting multiple diseases through gamma -secretase" will evaluate the use of gamma -secretase inhibitors to target CNS disease, inflammatory responses and carcinogenesis. The molecular target that forms the focus of this study, gamma -secretase, has been the subject of intense investigation by the academic and industrial communities for its importance in the pathogenesis of Alzheimer's disease (AD). Gamma-secretase has several targets including the Notch family of proteins. Therefore inhibition of gamma -secretase is likely to have broad effects on cellular physiology. Several classes of drugs have been developed which inhibit gamma -secretase with variable potency and specificity. Based on preliminary data presented in this application, we suggest that targeting gamma -secretase is likely to have bread ranging effects in the CNS, immune system as well as in developing tumors and pose experiments to test these predictions. In Project 1, we will develop biomarkers to evaluate the effect of gamma -secretase inhibition on Notch and correlate these data with reduction in the A-beta fragment of amyloid precursor protein. The role of Notch signaling in demyelination also will be studied. In Project 2, the effects of gamma -secretase inhibition will be studied in a variety of in vivo immune responses including immune response to two pathogens, antibody production and autoimmunity. In Project 3, we will determine the effect of gamma -secretase inhibition on the maintenance of the neoplastic phenotype. Overall this Program describes an interdisciplinary approach directed at establishing the efficacy of targeting an enzymatic activity, gamma -secretase in multiple disease models.